Method for producing and screening mass-coded combinatorial libraries for drug discovery and target validation

ABSTRACT

The present invention provides a method for producing a mass-coded combinatorial library comprising a set of compounds having the general formula X(Y) n , where X is a scaffold, each Y is, independently, a peripheral moiety, and n is an integer greater than 1. The method comprises selecting a peripheral moiety precursor subset from a peripheral moiety precursor set. The subset includes a sufficient number of peripheral moiety precursors that at least about 50 distinct combinations of n peripheral moieties derived from the peripheral moiety precursors in the subset exist. The subset of peripheral moiety precursors is selected so that at least about 90% of all possible combinations of n peripheral moieties derived from the subset have a molecular mass sum which is distinct from the molecular mass sums of all of the other combinations of n peripheral moieties. The method further comprises contacting the peripheral moiety precursor subset with a scaffold precursor which has n reactive groups. Methods of use of the mass-coded combinatorial library produced by this method for identifying a ligand to a particular biomolecule are also disclosed.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/070,456, filed Jan. 5, 1998, the contents of which are incorporatedherein by reference in their entirety.

BACKGROUND OF THE INVENTION

Genomics is identifying the genes responsible for all human functionsand diseases. With 80,000 genes in the human genome, the thousands ofgenes involved in development, stature, intelligence, and other featuresof a human being are being defined. Humans suffer from hundreds ofinherited and infectious diseases, and the genes involved in such arealso being identified. Proteins encoded by all these genes are targetsfor therapeutic drugs. However, drugs that can be applied to humanfunction and disease will not simply emerge from genomic information.Conventional drug development for a single disease is a lengthy, tediousand extremely expensive process. Technologies that eliminate the majorhurdles facing drug development in the post-genomic era would be ofsubstantial value.

SUMMARY OF THE INVENTION

The present invention provides a method for producing a mass-coded setof chemical compounds having the general formula X(Y)_(n), where X is ascaffold, each Y is, independently, a peripheral moiety, and n is aninteger greater than 1, typically from 2 to about 6. The methodcomprises selecting a peripheral moiety precursor subset from aperipheral moiety precursor set. The subset includes a sufficient numberof peripheral moiety precursors that at least about 50, 100, 250 or 500distinct combinations of n peripheral moieties derived from theperipheral moiety precursors in the subset exist. The subset ofperipheral moiety precursors is selected so that at least about 90% ofall possible combinations of n peripheral moieties derived from thesubset of peripheral moiety precursors have a molecular mass sum whichis distinct from the molecular mass sums of all of the othercombinations of n peripheral moieties. The method further comprisescontacting the peripheral moiety precursor subset with a scaffoldprecursor which has n reactive groups, each of which is capable ofreacting with at least one peripheral moiety precursor to form acovalent bond. The peripheral moiety precursor subset is contacted withthe scaffold precursor under conditions sufficient for the reaction ofeach reactive group with a peripheral moiety precursor, resulting in amass-coded set of compounds of the general formula X(Y)_(n).

In another embodiment, the invention provides a method of identifying amember or members of a mass-coded combinatorial library which areligands for a biomolecule, for example, a protein or a nucleic acidmolecule, such as DNA or RNA. The method comprises the steps of (1)contacting the biomolecule with the mass-coded molecular library,whereby members of the mass-coded molecular library which are ligandsfor the biomolecule bind to the biomolecule to form biomolecule-ligandcomplexes and members of the mass-coded library which are not ligandsfor the biomolecule remain unbound; (2) separating thebiomolecule-ligand complexes from the unbound members of the mass-codedmolecular library; (3) dissociating the biomolecule-ligand complexes;and (4) determining the molecular mass of each ligand to identify theset of n peripheral moieties present in each ligand.

In a further embodiment, the invention provides a method for identifyinga member or members of a mass-coded molecular library which are ligandsfor a biomolecule and bind to the biomolecule at the binding site of aligand known to bind the biomolecule (a known ligand). The methodcomprises the steps of: (1) contacting the biomolecule with themass-coded molecular library, so that members of the mass-codedmolecular library which are ligands for the biomolecule bind to thebiomolecule to form biomolecule-ligand complexes and members of themass-coded library which are not ligands for the biomolecule remainunbound; (2) separating the biomolecule-ligand complexes from theunbound members of the mass-coded molecular library; (3) contacting thebiomolecule-ligand complexes with a ligand known to bind thebiomolecule, to dissociate biomolecule-ligand complexes in which theligand binds to the biomolecule at the binding site of the known ligand,thereby forming biomolecule-known ligand complexes and dissociatedligands; (4) separating the dissociated ligands and biomolecule-ligandcomplexes; and (5) determining the molecular mass of each dissociatedligand to identify the set of n peripheral moieties present in eachdissociated ligand.

In a yet further embodiment, the invention provides a method foridentifying a member or members of a mass-coded combinatorial librarywhich are ligands for a first biomolecule but are not ligands for asecond biomolecule. The method comprises the steps of: (1) contactingthe first biomolecule with the mass-coded molecular library, wherebymembers of the mass-coded molecular library which are ligands for thefirst biomolecule bind to the first biomolecule to form firstbiomolecule-ligand complexes and members of the mass-coded library whichare not ligands for the first biomolecule remain unbound; (2) separatingthe first biomolecule-ligand complexes from the unbound members of themass-coded molecular library; (3) dissociating the firstbiomolecule-ligand complexes; (4) determining the molecular mass of eachligand for the first biomolecule; (5) contacting the second biomoleculewith the mass-coded molecular library, whereby members of the mass-codedmolecular library which are ligands for the second biomolecule bind tothe second biomolecule to form second biomolecule-ligand complexes andmembers of the mass-coded library which are not ligands for the secondbiomolecule remain unbound; (6) separating the second biomolecule-ligandcomplexes from the unbound members of the mass-coded molecular library;(7) dissociating the second biomolecule-ligand complexes; (8)determining the molecular mass of each ligand for the secondbiomolecule; and (9) determining which molecular masses determined instep (4) are not determined in step (8). This provides the molecularmasses of members of the mass-coded combinatorial library which areligands for the first biomolecule, but are not ligands for the secondbiomolecule.

In another embodiment, the method for identifying a member or members ofa mass-coded combinatorial library which are ligands for a firstbiomolecule but are not ligands for a second biomolecule comprises thesteps of: (1) contacting the second biomolecule with the mass-codedmolecular library, so that members of the mass-coded molecular librarywhich are ligands for the second biomolecule bind to the secondbiomolecule to form second biomolecule-ligand complexes and members ofthe mass-coded library which are not ligands for the second biomoleculeremain unbound; (2) separating the second biomolecule-ligand complexesfrom the unbound members of the mass-coded molecular library; (3)contacting the first biomolecule with the unbound members of themass-coded molecular library of step (2), whereby members of themass-coded molecular library which are ligands for the first biomoleculebind to the first biomolecule to form first biomolecule-ligand complexesand members of the mass-coded library which are not ligands for thefirst biomolecule remain unbound; (4) dissociating the firstbiomolecule-ligand complexes; and (5) determining the molecular mass ofeach ligand for the first biomolecule. Each molecular mass determinedcorresponds to a set of n peripheral moieties present in a ligand forthe first biomolecule which is not a ligand for the second biomolecule.

In yet another embodiment, the present invention relates to a method foridentifying a member of a mass-coded combinatorial library which is aligand for a biomolecule and assessing the the effect of the binding ofthe ligand to the biomolecule. The method comprises the steps of:contacting the biomolecule with the mass-coded molecular library,whereby members of the mass-coded molecular library which are ligandsfor the biomolecule bind to the biomolecule to form biomolecule-ligandcomplexes and members of the mass-coded library which are not ligandsfor the biomolecule remain unbound; separating the biomolecule-ligandcomplexes from the unbound members of the mass-coded molecular library;dissociating the biomolecule-ligand complexes; determining the molecularmass of each ligand to identify the set of n peripheral moieties presentin each ligand. The molecular mass of each ligand corresponds to a setof n peripheral moieties present in that ligand, thereby identifying amember of the mass-coded combinatorial library which is a ligand for thebiomolecule. The method further comprisies assessing in an in vivo or invitro assay the effect of the binding of the ligand to the biomoleculeon the function of the biomolecule.

The method of the invention allows rapid production of mass-codedcombinatorial libraries comprising large numbers of compounds. Themass-coding enables the identification of individual combinations ofscaffold and peripheral moieties by molecular mass. The librariesprepared by the method of the invention also allow the rapididentification of compounds which are ligands for a given biomolecule.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B are flow charts illustrating a procedure and alternativeprocedure, respectively, for selecting a subset of peripheral moietyprecursors from among a larger set of peripheral moiety precursors forthe production of a mass-coded combinatorial library.

FIG. 2A is a graph illustrating the mass redundancy of the combinatoriallibraries resulting from a computer selected set of peripheral moietyprecursors selected using a mass-coding algorithm.

FIG. 2B is a graph illustrating the mass redundancy of the combinatoriallibraries resulting from a set of peripheral moiety precursors selectedrandomly.

FIG. 2C presents graphs illustrating the mass redundancy of thecombinatorial libraries resulting from

-   (1) a computer optimized set of peripheral moiety precursors    selected using a mass-coding algorithm ( . . . ) and-   (2) a set of peripheral moiety precursors selected randomly (−).

FIG. 3 is a schematic diagram of a computer system employing a digitalprocessor assembly embodying the invention method of selecting a subsetof peripheral moiety precursors which minimize or eliminate massredundancy in a library.

DETAILED DESCRIPTION OF THE INVENTION

The major hurdles in drug development include a need for: 1)combinatorial chemistry technology that enables rapid production ofnearly unlimited numbers of compounds while incorporating the ability toidentify efficiently single chemical compounds that bind tightly to aspecific biomolecule target, such as a protein or nucleic acid molecule;2) extremely efficient target-based screening technologies that permitrapid identification of chemical compounds within a large librarymixture that become tightly associated with a target biomolecule, evenwhen the function of that biomolecule is not well understood and 3) aninformation data set that describes how chemical components interactwith biomolecules of medical importance.

The present invention provides a method of producing a mass-coded set ofcompounds, such as a mass-coded combinatorial library. The compounds areof the general formula X(Y)_(n), wherein X is a scaffold, each Y is aperipheral moiety and n is an integer greater than 1, typically from 2to about 6. The term “scaffold”, as used herein, refers to a molecularfragment to which two or more peripheral moieties are attached via acovalent bond. The scaffold is a molecular fragment which is common toeach member of the mass-coded set of compounds. The term “peripheralmoiety”, as used herein, refers to a molecular fragment which is bondedto a scaffold. Each member of the set of mass-coded compounds willinclude a combination of n peripheral moieties bonded to the scaffoldand this set of compounds forms a mass coded combinatorial library.

The term “combination”, as used herein, refers to all permutations of mmoieties having n members where m is an integer greater than 2, n is aninteger greater than 1 and m is greater than or equal to n, such that:

-   (1) Permutations having n members in which a given moiety is present    from 0 to n times are included.-   (2) Permutations having the same n moieties but ordered differently    are included once and only once.    The number of combinations of all permutations of m moieties having    n members may be calculated from the formula:    Combinations=k!/((k−n)!*n!) where k=m+(n−1)    For example, the combinations of the four moieties labeled A, B, C,    D which have 3 members are: A A A; A A B; A A C; A A D; A B B; A B    C; A B D; A C C; A C D; A D D; B B B; B B C; B B D; B C C; B C D; B    D D; C C C; C C D; C D D and D D D. B A A and A B A, for example,    are not counted as separate combinations; only A A B is counted. In    this example, m=4, n=3 and the number of combinations is given by    6!/((6−3)!*3!)=20.

The terms “mass-coded set of compounds” and “mass-coded combinatoriallibrary”, as used herein, refer to a set of compounds of the formulaXY_(n), where X is a scaffold, each Y is, independently, a peripheralmoiety and n is an integer greater than 1, typically from 2 to about 6.Such a set of compounds is synthesized as a mixture by the combinationof a set of peripheral moiety precursors with a scaffold precursor, andis designed to possess minimum mass redundancy, given the requirementthat a fixed number (subset) of peripheral moiety precursors must bechosen from a set of available peripheral moiety precursors.

The term “mass” or “molecular mass”, as used herein, refers to the exactmass of a molecule or collection of chemical moieties in which each atomis the most abundant naturally occurring isotope for the particularelement. Exact masses and their determination by mass spectrometry arediscussed by Pretsch et al., Tables of Spectral Data for StructureDetermination of Organic Compounds, second edition, Springer-Verlag(1989), and Holden et al., Pure Appl. Chem. 55: 1119-1136 (1983), thecontents of each of which are incorporated herein by reference in theirentirety.

“Minimum mass redundancy”, as the term is used herein, is exhibited by aset of compounds of the formula X(Y)_(n) formed by reaction of ascaffold precursor having n reactive groups, where n is an integergreater than 1, typically from 2 to about 6, with a subset of peripheralmoiety precursors in which at least about 90% of the possiblecombinations of n peripheral moieties derived from the subset ofperipheral moiety precursors have a molecular mass sum which is distinctfrom the molecular mass sum of any other combination of n peripheralmoieties derived from the subset. The molecular mass sum of acombination of peripheral moieties is the sum of the masses of eachperipheral moiety within the combination. For the present purposes, twomolecular masses are distinct if they can be distinguished by massspectrometry or high resolution mass spectrometry. For example,molecular masses which differ by at least 0.001 atomic mass units can bedistinguished by high resolution mass spectrometry.

It is to be understood that the molecular mass sum of the combination ofthe n peripheral moieties in a particular compound of the formulaX(Y)_(n) is the collective contribution of the n peripheral moieties tothe molecular mass of the compound. As each compound within the setincludes a constant scaffold, the difference in the molecular masses oftwo compounds within the mass-coded set of compounds is the differencein the molecular mass sums of the set of peripheral moieties in eachcompound.

The method of the invention comprises selecting a peripheral moietyprecursor subset from a larger peripheral moiety precursor set. Detailsof the preferred selection process are discussed later with reference toFIGS. 1A, 1B and 3. The subset includes a sufficient number ofperipheral moiety precursors so that, in one embodiment, at least about50 distinct combinations of n peripheral moieties derived from theperipheral moiety precursors in the subset can be formed. In anotherembodiment, at least about 100 distinct combinations of n peripheralmoieties can be formed. In a further embodiment, at least about 250distinct combinations of n peripheral moiety precursors can be formed,and, in yet another embodiment, at least about 500 distinct combinationsof n peripheral moieties can be formed.

The subset of peripheral moiety precursors is selected so that at leastabout 90% of all possible combinations of n peripheral moieties derivedfrom the subset have a molecular mass sum which is distinct from themolecular mass sums of all of the other combinations of n peripheralmoieties. The method further comprises contacting the peripheral moietyprecursor subset with a scaffold precursor which has n reactive groups,each of which is capable of reacting with at least one peripheral moietyprecursor to form a covalent bond. The peripheral moiety precursorsubset is contacted with the scaffold precursor under conditionssufficient for the reaction of each reactive group with a peripheralmoiety precursor, resulting in a mass-coded set of compounds.

In one embodiment, at least about 95% of all possible combinations of nperipheral moieties derived from the peripheral moiety precursor subsethave a molecular mass sum which is distinct from the molecular mass sumsof all of the other combinations of n peripheral moieties. In anotherembodiment, each of the possible combinations of n peripheral moietiesderived from the subset has a molecular mass sum which is distinct fromthe molecular mass sums of all of the other combinations of n peripheralmoieties.

The scaffold precursor can be any molecule comprising two or morereactive groups which are capable of reacting with a peripheral moietyprecursor reactive group to form a covalent bond. For example, suitablescaffold precursors can have a wide range of sizes, shapes, degrees offlexibility and charges. The reactive groups should be incapable ofintramolecular reaction under the conditions employed. Further, ascaffold precursor molecule should not react with another scaffoldprecursor molecule under the conditions employed. The scaffold precursorcan also include any additional functional groups which are masked orprotected or which do not interfere with the reaction of the reactivegroups with the peripheral moiety precursors.

Preferably, the scaffold precursor comprises one or more saturated,partially unsaturated or aromatic cyclic groups, such as a cyclichydrocarbon or heterocyclic group. In scaffold precursors comprising twoor more cyclic groups, the cyclic groups can be fused, connected via adirect bond or connected via an intervening group, such as an oxygenatom, an NH group or a C₁₋₆-alkylene group. At least one cyclic group issubstituted by one or more reactive groups. The reactive groups can beattached to the cyclic group directly or via an intervening group, suchas a C₁₋₆-alkylene group, preferably a methylene group.

Examples of suitable scaffold precursors include reactivegroup-substituted benzene, biphenyl, cyclohexane, bipyridyl,N-phenylpyrrole, diphenyl ether, naphthalene and benzophenone. Othersuitable classes of scaffold precursors are shown below.

In these examples, each of the indicated substituents R is,independently, a reactive group, and the scaffold precursor can includeone or more additional functional groups which are either (1) masked orprotected to prevent their reaction with a peripheral moiety precursor(e.g., scaffold precursors f and g, above) or (2) do not react eitherwith R or with a peripheral moiety precursor under the given reactionconditions (e.g., scaffold precursor h, above, in which R═C(O)O(C₆F₅)and the peripheral moiety precursors include primary amino groups).

A peripheral moiety precursor is a compound which includes a reactivegroup which is complementary to one or more of the reactive groups ofthe scaffold precursor. In addition to the reactive group, a peripheralmoiety precursor can include a wide variety of structural features. Forexample, the peripheral moiety precursor can include one or morefunctional groups in addition to the reactive group. Any additionalfunctional group should be appropriately masked or not interfere withthe reaction between the scaffold precursor and the peripheral moietyprecursor. In addition, two peripheral moiety precursors should notreact together under the conditions employed. For example, a subset ofperipheral moiety precursors can include, in addition to the reactivegroups, functionalities selected from groups spanning a range of charge,hydrophobicity/hydrophilicity, and sizes. For example, the peripheralmoiety precursor can include a negative charge, a positive charge, ahydrophilic group or a hydrophobic group.

In addition to the reactive groups, peripheral moiety precursors caninclude, for example, functionalities selected from among amino acidside chains, a nucleotide base or nucleotide base analogue, sugarmoieties, sulfonamides, peptidomimetic groups, charged or polarfunctional groups, alkyl groups and aryl groups.

For the present purposes, two reactive groups are complementary if theyare capable of reacting together to form a covalent bond. In a preferredembodiment, the bond forming reactions occur rapidly under ambientconditions without substantial formation of side products. Preferably, agiven reactive group will react with a given complementary reactivegroup exactly once.

In one embodiment, the reactive group of the scaffold precursor and thereactive group of the peripheral moiety precursor react, for example,via nucleophilic substitution, to form a covalent bond. In oneembodiment, the reactive group of the scaffold precursor is anelectrophilic group and the reactive group of the peripheral moietyprecursor is a nucleophilic group. In another embodiment, the reactivegroup of the scaffold precursor is a nucleophilic group, while thereactive group of the peripheral moiety precursor is an electrophilicgroup.

Complementary electrophilic and nucleophilic groups include any twogroups which react via nucleophilic substitution under suitableconditions to form a covalent bond. A variety of suitable bond-formingreactions are known in the art. See, for example, March, AdvancedOrganic Chemistry, fourth edition, New York: John Wiley and Sons (1992),Chapters 10 to 16; Carey and Sundberg, Advanced Organic Chemistry, PartB, Plenum (1990), Chapters 1-11; and Collman et al., Principles andApplications of Organotransition Metal Chemistry, University ScienceBooks, Mill Valley, Calif. (1987), Chapters 13 to 20; each of which isincorporated herein by reference in its entirety. Examples of suitableelectrophilic groups include reactive carbonyl groups, such as carbonylchloride (acyl chloride) and carbonyl pentafluorophenyl ester groups,reactive sulfonyl groups, such as the sulfonyl chloride group, andreactive phosphonyl groups. Other electrophilic groups which can be usedinclude terminal epoxide groups and the isocyanate group. Suitablenucleophilic groups include primary and secondary amino groups andalcohol (hydroxyl) groups.

Examples of suitable scaffold precursors with specified reactive groupsare shown below.

In these examples, each R is, independently, an additional reactivegroup which can be the same as the specified reactive group or adifferent group.

Illustrated below are examples of suitable peripheral moiety precursorshaving amino groups.

R in this case is an amino acid side chain, ^(t)Boc is^(t)butoxycarbonyl, Ac is acetyl and ^(t)Bu is tertiary butyl.

Examples of scaffold precursors and peripheral moiety precursors whichhave complementary reactive groups include the following, which areprovided for the purposes of illustration and are not to be construed aslimiting in any way:

-   1. The scaffold precursor includes from two to about six reactive    carbonyl groups, reactive sulfonyl groups or reactive phosphonyl    groups, or a combination thereof. Each peripheral moiety precursor    includes a primary or secondary amino group which reacts with the    scaffold precursor to form an amide, sulfonamide or phosphonamidate    bond.-   2. The scaffold precursor includes from two to about six primary or    secondary amino groups or a combination thereof. Each peripheral    moiety precursor includes a reactive carbonyl group, a reactive    sulfonyl group or a reactive phosphonyl group.-   3. The scaffold precursor includes from two to about six terminal    epoxide groups. Each peripheral moiety precursor includes a primary    or secondary amino group. In the presence of a suitable Lewis acid,    the scaffold precursor and the peripheral moiety precursors react to    form β-amino alcohols.-   4. The scaffold precursor includes from two to about six primary or    secondary amino groups. Each peripheral moiety precursor contains a    terminal epoxide group.-   5. The scaffold precursor includes from two to about six isocyanate    groups. Each peripheral moiety precursor contains a primary or    secondary amino group which reacts with the scaffold precursor to    form a urea.-   6. The scaffold precursor includes from two to about six primary or    secondary amino groups, or a combination thereof. Each peripheral    moiety precursor contains an isocyanate group.-   7. The scaffold precursor includes from two to about six isocyanate    groups. Each peripheral moiety precursor contains an alcohol group    which reacts with the scaffold precursor to form a carbamate.-   8. The scaffold precursor includes from 2 to about 6 aromatic    bromides. Each peripheral moiety precursor is an organo-tributyl-tin    compound. The scaffold precursor and the peripheral moiety    precursors are reacted in the presence of a suitable palladium    catalyst to form one or more carbon-carbon bonds.-   9. The scaffold precursor includes from 2 to about 6 aromatic    halides or triflates. Each peripheral moiety precursor includes a    primary or secondary amino groups. The scaffold precursor and the    peripheral moiety precursors are reacted in the presence of a    suitable palladium catalyst to form one or more carbon-nitrogen    bonds.-   10. The scaffold precursor includes from two to about six amino    groups. Each peripheral moiety precursor contains an aldehyde or    ketone group which reacts with the scaffold precursor under reducing    conditions (reductive amination) to form an amine.-   11. The scaffold precursor includes from two to about six aldehyde    or ketone groups. Each peripheral moiety precursor contains an amino    group which reacts with the scaffold precursor under reducing    conditions (reductive amination) to form an amine.-   12. The scaffold precursor includes from two to about six    phosphorous ylide groups. Each peripheral moiety precursor contains    an aldehyde or ketone group which reacts with the scaffold precursor    (Wittig type reaction) to form an alkene.-   13. The scaffold precursor includes from two to about six aldehyde    or ketone groups. Each peripheral moiety precursor contains a    phosphorous ylide group which reacts with the scaffold precursor    (Wittig type reaction) to form an alkene.

The scaffold is that portion of the scaffold precursor which remainsafter each reactive group of the scaffold precursor has reacted with aperipheral moiety precursor. A peripheral moiety is that portion of theperipheral moiety precursor which is bonded to the scaffold followingthe bond-forming reaction. A peripheral moiety which results from thereaction of a particular peripheral moiety precursor with a reactivefunctional group of a scaffold precursor is said to be “derived” fromthat peripheral moiety precursor.

A peripheral moiety precursor can include one or more functional groupsin addition to the reactive group. One or more of these additionalfunctional groups can be protected to prevent undesired reactions ofthese functional groups. Suitable protecting groups are known in the artfor a variety of functional groups (Greene and Wuts, Protective Groupsin Organic Synthesis, second edition, New York: John Wiley and Sons(1991), incorporated herein by reference). Particularly usefulprotecting groups include t-butyl esters and ethers, acetals, tritylethers and amines, acetyl esters, trimethylsilyl ethers andtrichloroethyl ethers and esters.

The compounds within the set are mass-coded as a result of the selectionof a subset of suitable peripheral moiety precursors. The subset ofperipheral moiety precursors is selected such that for a scaffoldprecursor having n reactive groups, where n is an integer from 2 toabout 6, there exist at least about 50, 100, 250 or 500 differentcombinations of n peripheral moieties derived from the peripheral moietyprecursor subset. At least about 90% of the possible combinations of nperipheral moieties derived from the peripheral moiety precursors withinthe subset will have a distinct mass sum. In one embodiment, theselection of suitable peripheral moiety precursors for the production ofa mass-coded set of compounds includes one or more automated stepsutilizing hardware apparatus, software apparatus or any combinationthereof. In the preferred embodiment, a digital processor assemblyemploys a suitable software routine which selects a subset of peripheralmoiety precursors which minimize or eliminate mass redundancy in thelibrary. FIG. 3 is illustrative of such apparatus employing a digitalprocessor assembly for carrying out the present invention method.

Referring to FIG. 3, there is shown a computer system 25 formed of (a) adigital processor 11 having working memory 17 for executing programs,routines, procedures and the like, (b) input means 21 coupled to thedigital processor 11 for providing data, parameters and the like tosupport execution of the programs, routines and/or procedures in thedigital processor working memory 17, and (c) output means 23 coupled tothe digital processor 11 for displaying results, prompts, messages andthe like from operation of the digital processor 11. The input means 21include a keyboard, mouse and the like common in the art. The outputmeans 23 include a viewing monitor, printer and the like common in theart. The invention software routine 27 is executed in the working memory17 by the digital processor 11 as follows.

First, a user interface prompts the end-user to input indications of aninitial set 13 of peripheral moiety precursors and the exact masses ofthe peripheral moieties which are derived therefrom. This initial set 13may be copied, transferred or otherwise obtained from a database orother source such as is known in the art. The user interface alsoobtains from the end-user a set of user determined/desired criteria 19.In the preferred embodiment, the user selected criteria 19 includes (i)the total count j of peripheral moiety precursors in the initial set,(ii) the value of n indicating the number of reactive groups of asubject scaffold precursor for which the invention software routine 27is to select a subset of peripheral moiety precursors from the inputinitial set 13 and (iii) the number of members of the subset, k.Preferably, the user interface enables the end-user to interactivelyprovide the user selected criteria 19 through the input means 21 asindicated at 15 in FIG. 3.

The digital processor 11 is responsive to the foregoing input and storesthe indications of the initial set 13 of peripheral moiety precursors ina memory area 29 or data storage system associated locally or off diskwith the software routine 27. That is, the memory area 29 or datastorage system supports the invention software routine 27. For eachperipheral moiety precursor in the initial set 13 as indicated in memoryarea 29, an identifier and indication of respective exact mass of thethe peripheral moiety derived from the peripheral moiety precursor isprovided to the software routine 27. Upon receipt of the peripheralmoiety precursor identifiers, indications of exact mass, and userselected criteria (n, j and k), the software routine 27 determines andgenerates a subset of k s peripheral moiety precursors which minimize oreliminate mass redundancy in a resulting library of compounds of theformula XY_(n), wherein X is a scaffold, each Y is, independently, aperipheral moiety, and n is an integer greater than 1, typically from 2to about 6. Preferably, the software routine 27 determines a subset ofperipheral moiety precursors in which at least about 90% of the possiblecombinations of n peripheral moieties derived from the subset have adistinct mass sum. The details of the software routine 27 employed inthe preferred embodiment are discussed next for purposes of illustrationand not limitation. It is understood that other software or firmwareroutines for accomplishing the present invention method of selecting asubset of the initial set 13 of peripheral moiety precursors aresuitable and within the purview of one skilled in the art given thisdisclosure.

A typical situation involves a scaffold precursor with n reactivegroups, where n is an integer, a set of j peripheral moiety precursors,where j is an integer 6 or greater, where the peripheral moietiesderived from the peripheral moiety precursors have molecular masses y₁,y₂, . . . y_(j). An example of a software routine which can be employedto select a suitable subset of k peripheral moiety precursors (k≦j) fromthe set of j peripheral moiety precursors includes the following steps:

-   -   1. From an initial set of j peripheral moiety precursors, choose        every set of two peripheral moiety precursors. If y_(a)=y_(b),        randomly remove either y_(a) or y_(b).    -   2. From the remaining set of peripheral moiety precursors,        choose every set of four peripheral moiety precursors. If        y_(a)+y_(b)=y_(c)+y_(d), randomly remove either y_(a), y_(b),        y_(c) or y_(d).    -   3. From the remaining set of peripheral moiety precursors,        choose every set of six peripheral moiety precursors. If        y_(a)+y_(b)+y_(c)=y_(d)+y_(e)+y_(f), randomly remove either        y_(a), y_(b), y_(c), y_(d), y_(e) or y_(f).

-   If at any step 1 through 3 the remaining number of peripheral moiety    precursors becomes <k, then there is no mass coded subset k which    can be made from set j, and a new set j must be employed.

-   4. From the remaining computer selected set of peripheral moiety    precursors, choose any or all subsets of k peripheral moiety    precursors.

-   5. Generate all possible combinations of n peripheral moiety    precursors from this subset.

-   6. If the % mass redundancy of the resulting set of combinations is    found to be unacceptable, repeat step until a desired mass coded    library has been obtained or no further possible combinations of    peripheral moiety precursors remain. In the latter case, begin again    with step 1.

Once an above subset of mass-coded peripheral moiety precursors isdetermined, the scaffold precursor is contacted with the subset ofcomplementary peripheral moiety precursors under conditions suitable forbond-forming reactions to occur between the peripheral moiety precursorsand the scaffold precursor. The mass-coded set of compounds is,preferably, synthesized in solution as a combinatorial library.

The foregoing selection of a subset from a larger peripheral moietyprecursor set and generation of a mass-coded set of compounds using theselected subset is more generally illustrated in FIGS. 1A and 1B.Referring to FIG. 1A, the larger set of peripheral moiety precursors isprovided at 31 from known sources. The end-user (e.g., chemist) selectsan initial set of j peripheral moiety precursors from the larger set 31at step 33. Typically the chemist chooses all of the larger set to formthe initial set at 33. The invention mass coding selection procedure 35is applied to the initial set. The result of the mass-coding procedure35 is a subset 37 of peripheral moiety precursors that satisfies themass-coding criteria outlined above. In step 39, this subset ofperipheral moiety precursors is used to generate all theoretical subsetsof of k peripheral moiety precursors. Also in step 39, the massredundancies of the libraries obtained from all theoretical subsets of kperipheral moieties are calculated, and only those subsets which yieldmass-coded libraries, as defined above, are passed to 41. The net resultis one or more subsets 41 of k peripheral moiety precursors in whichthere are 50, 100, 250, or 500 distinct combinations of n peripheralmoiety precursors in a given subset and at least 90% of all possiblecombinations of n peripheral moieties derived from a given subset have amolecular mass sum which is distinct from the molecular mass sums of allof the other combinations of n peripheral moieties, as discussed above.The subset(s) 41 of peripheral moiety precursors would subsequentlyyield mass-coded sets of compounds when contacted with an appropriatescaffold precursor in the manner discussed above.

As an alternative to the single-step application of the inventionmass-coding selection procedure 35 in FIG. 1A, multiple or steppedapplication of procedure 35 is suitable and in certain cases may beadvantageous. For instance, using mass-coding procedures at each levelallows for rapid sorting into distinct sets, each of which may yieldoptimal mass-coding. During the mass-coding process, certain criteriareduce the set size as it is passed into the next layer throughmass-coding. This multi-layer approach yields advantages in speed andthe elimination of mass redundancy.

Multiple application of mass-coding selection procedure 35 on initialset 33 is illustrated in FIG. 1B. Here initial set 33 is divided intoplural parts (the starting larger set of peripheral moiety precursors 31and chemist selection 33 being similar to that in FIG. 1A). Themass-coding selection procedure 35 is applied to each plural part andresults in intermediate resultant sets 43A, 43B, 43C. The mass-codedselection procedure 35 is applied in a second round/level but this timewith intermediate resultant sets 43A, 43B, 43C. This produces final sets45A, 45B, 45C. Step 39 is as in FIG. 1A and generates the subsets 47A,47B, 47C of k peripheral moiety precursors that would subsequently yieldmass-coded stes of compounds when contacted with an appropriate scaffoldprecursor in a manner discussed above.

It is understood that other variations between the approach illustratedin FIG. 1A and that in FIG. 1B are within the purview of one skilled inthe art. The foregoing discussion and Figures are for purposes ofillustrating and not limiting the present invention method.

In one embodiment, the scaffold precursor is contacted with all membersof the peripheral moiety precursor subset simultaneously. In general, ascaffold precursor having n reactive groups, where n is an integer from2 to about 6, will be contacted with at least about n molar equivalentsrelative to the scaffold precursor of peripheral moiety precursors fromthe selected subset. For example, the scaffold precursor can becontacted with a solution comprising each member of the subset inapproximately equal concentrations. For example, if the scaffoldprecursor includes n reactive groups, where n is an integer greater than1, and the number of peripheral moiety precursors in the subset isdenoted by p, the scaffold precursor can be contacted with about n/p toabout (1.1)n/p molar equivalents of each peripheral moiety precursor.

In another embodiment, the scaffold precursor is contacted with themembers of the peripheral moiety precursor subset sequentially. Thisresults in the formation of intermediate partially reacted scaffoldprecursor molecules which include at least one peripheral moiety and atleast one reactive group. For example, the scaffold precursor can becontacted with one or more peripheral moiety precursors under conditionssuitable for bond formation to occur. The resulting intermediates canthen be contacted with one or more additional peripheral moietyprecursors under suitable conditions for bond formation to occur. Thesesteps can be repeated until each scaffold precursor reactive group hasreacted with a peripheral moiety precursor.

In one embodiment, the reactive groups of the scaffold precursor canreact sequentially with the subset of peripheral moiety precursors usinga suitable reactive group protection/deprotection scheme. For example,the scaffold precursor can include two or more sets of reactive groups,where one set is unprotected and another set is protected, or where twosets are masked by different protecting groups. An example is the use ofthe scaffold precursor

which contains one unprotected reactive group and two protected reactivegroups. In this case, the unprotected pentafluorophenyl ester can reactwith a peripheral moiety precursor first (e.g., a primary amine). Eitherthe Cl₃CCH₂O-protected group or the benzyloxy-protected group can thenbe deprotected using standard methods and reacted with a set ofperipheral moiety precursors. Finally, the remaining protected group orgroups can be deprotected and reacted with a set of peripheral moietyprecursors.

Following the reaction of each scaffold precursor reactive group with aperipheral moiety precursor, any peripheral moiety having a protectedfunctional group can be deprotected using methods known in the art.

The ability to identify individual scaffold plus peripheral moietycombinations derived from such a mixture is a consequence of themass-coding of the library and the ability of mass spectrometry toidentify a molecular mass. This allows the identification of individualscaffold plus peripheral moiety combinations within the set which have aparticular activity, such as binding to a particular biomolecule.

In one embodiment, the present invention provides a method foridentifying a compound or compounds within a mass-coded combinatoriallibrary which bind to, or are ligands for, a biomolecule, such as aprotein or nucleic acid molecule. The mass-coded combinatorial librarycan be produced, for example, by the method of the invention disclosedabove. The target biomolecule, such as a protein, is contacted with themass-coded combinatorial library, and, if any members of the library areligands for the biomolecule, biomolecule-ligand complexes form.Compounds which do not bind the biomolecule are separated from thebiomolecule-ligand complexes. The biomolecule-ligand complexes aredissociated and the ligands are separated and their molecular masses aredetermined. Due to the mass-coding of the combinatorial library, a givenmolecular mass is characteristic of a unique combination of peripheralmoieties or only a small number of such combinations. Thus, a ligand'smolecular mass allows the determination of its composition.

In one embodiment, the target is immobilized on a solid support by anyknown immobilization technique. The solid support can be, for example, awater-insoluble matrix contained within a chromatography column or amembrane. The mass-coded set of compounds can be applied to awater-insoluble matrix contained within a chromatography column. Thecolumn is then washed to remove non-specific binders. Target-boundcompounds (ligands) can then be dissociated by changing the pH, saltconcentration, organic solvent concentration, or other methods, such ascompetition with a known ligand to the target. The dissociated ligandsare injected directly onto a reverse phase column. The reverse phasecolumn acts as a concentrator/collector and can be interfaced directlyto a mass spectrometer, such as an electrospray mass spectrometer(ES-MS). Mass information provided by the mass spectrometer issufficient for identifying the combination of scaffold and peripheralmoieties within the ligand.

In another embodiment, the target is free in solution and is incubatedwith the mass-coded set of compounds. Compounds which bind to the target(ligands) are selectively isolated by a size separation step such as gelfiltration or ultrafiltration. In one embodiment, the mixture ofmass-coded compounds and the target biomolecule are passed through asize exclusion chromatography column (gel filtration), which separatesany ligand-target complexes from the unbound compounds. Theligand-target complexes are transferred to a reverse-phasechromatography column, which dissociates the ligands from the target.The dissociated ligands are then analyzed by mass spectrometry. Massinformation provided by the mass spectrometer is sufficient foridentifying the scaffold and peripheral moiety composition of theligand. This approach is particularly advantageous in situations whereimmobilization of the target may result in a loss of activity.

Once single ligands are identified by the above-described process,various levels of analysis can be applied to yield SAR information andto guide further optimization of the affinity, specificity andbioactivity of the ligand. For ligands derived from the same scaffold,three-dimensional molecular modeling can be employed to identifysignificant structural features common to the ligands, therebygenerating families of small-molecule ligands that presumably bind at acommon site on the target biomolecule.

In order to identify a consensus, highest affinity, ligand for aparticular binding site, this analysis should include a ranking of the-members of a given ligand family with respect to their affinities forthe target. This process can provide this information by identifyingboth low and high affinity ligands for a target biomolecule in oneexperiment. For example, when the screen utilizes an immobilized target,the dissociation rate of the ligand is inversely correlated with thenumber of column volumes employed during of the ligand from its target.When the screen utilizes the target free in solution, weak affinityligands can be selected by using a higher concentration of the target.

Given that each mass-coded set of compounds is synthesized with alimited number of peripheral moiety precursors, the disclosed approachcan, in certain cases, identify a superior ligand which combinesstructural features of molecules synthesized in separate libraries.

When possible, the analysis of ligand structural features is based oninformation regarding the target biomolecule's structure, wherein thehypothetical consensus ligand is computationally docked with theputative binding site. Further computational analysis can involve adynamic search of multiple lowest energy conformations, which allowscomparison of high affinity ligands that are derived from differentscaffolds. The end goal is the identification of both the optimalfunctionality and the optimal vectorial presentation of the peripheralmoieties that yields the highest binding affinity/specificity. This mayprovide the basis for the synthesis of an improved, second-generationscaffold.

Due to the modular design of the mass-coded compounds, computationalanalysis may identify the point of attachment on the scaffold that hasthe least functional importance with respect to affinity for the target.In many cases, the ligand will not be completely engulfed by the targetbiomolecule, and one peripheral moiety will be pointed away from thebiomolecule towards the bulk solvent. Three-dimensional alignment of afamily of ligands will reveal a high degree of functional variability atthe site that is presented to the solvent. Modification at this site canthen be used to optimize the affinity. For example, the noncriticalreactive site can be removed and replaced with a small unreactive group,such as a hydrogen atom or a methyl group. A set of compoundsstructurally identical except for the peripheral moiety at this positioncan be examined to identify compounds that most effectively inhibit orpromote the binding of another protein/DNA/RNA molecule. Also, theperipheral moiety at this position can be modified to link two ligandstogether. The joining of two ligands could in certain cases yield aligand with improved affinity and specificity, if one joins moleculesthat bind to adjacent sites, or yield a designed biomolecule dimerizer.

A variety of screening approaches can be used to obtain ligands thatpossess high affinity for one target but significantly weaker affinityfor another closely related target. One screening strategy is toidentify ligands for both biomolecules in parallel experiments and tosubsequently eliminate common ligands by a cross-referencing comparison.In this method, ligands for each biomolecule can be separatelyidentified as disclosed above. This method is compatible with bothimmobilized target biomolecules and target biomolecules free insolution.

For immobilized target biomolecules, another strategy is to add apreselection step that eliminates all ligands that bind to thenon-target biomolecule from the library. For example, a firstbiomolecule can be contacted with a mass-coded combinatorial library asdescribed above. Compounds which do not bond to the first biomoleculeare then separated from any first biomolecule-ligand complexes whichform. The second biomolecule is then contacted with the compounds whichdid not bind to the first biomolecule. Compounds which bind to thesecond biomolecule can be identified as described above and havesignificantly greater affinity for the second biomolecule than to thefirst biomolecule.

The screening approach detailed above can also be applied to identifyligands that selectively interact with an altered version of the samebiomolecule, wherein the first biomolecule is the unaltered biomoleculeand the second biomolecule is an altered or variant version of thebiomolecule. The second biomolecule can, for example, have an amino acidsequence which differs from the amino acid sequence of the firstbiomolecule by the insertion, deletion or substitution of one or moreamino acid residues. For example, the second biomolecule can include aspecific amino acid mutation that is linked to the progression of aparticular disease. Alternatively, the second biomolecule can alsodiffer from the first biomolecule in having a differentpost-translational modification, such as an extra site ofphosphorylation or glycosylation, or it may be truncated or aberrantlyfused with another biomolecule.

The screening approach detailed above can also serve as a method foridentifying small molecule ligands that bind at the same site on abiomolecule as another known, biologically relevant ligand. This knownligand can be another biomolecule, such as a protein or peptide, or itcan be a DNA or RNA molecule, or a substrate or cofactor involved in anenzymatic reaction. In one embodiment, the first and second biomoleculesare both proteins. The first protein is a complex of the protein and theknown ligand, while the second protein is the protein alone. Compoundswhich bind to the protein alone, but not to the complex of the proteinwith the known ligand, bind to the protein at the binding site of theknown ligand. This approach is especially well suited to the developmentof small molecule replacements of known therapeutic ligands, such aspeptides or proteins.

An advantage of the present method is that it can be used to identifychemical compounds that bind tightly to any biomolecule of interest,even when the function of that biomolecule is not well understood, as isoften the case with gene products defined through genomics, or when afunctional assay is not available. The screening technologies describedcan be miniaturized to provide massive parallel screening capabilities.

A ligand for a biomolecule of unknown function which is identified bythe method disclosed above can also be used to determine the biologicalfunction of the biomolecule. This is advantageous because although newgene sequences continue to be identified, the functions of the proteinsencoded by these sequences and the validity of these proteins as targetsfor new drug discovery and development are difficult to determine andrepresent perhaps the most significant obstacle to applying genomicinformation to the treatment of disease. Target-specific ligandsobtained through the process described in this invention can beeffectively employed in whole cell biological assays or in appropriateanimal models to understand both the function of the target protein andthe validity of the target protein for therapeutic intervention. Thisapproach can also confirm that the target is specifically amenable tosmall molecule drug discovery. The ligands obtained through the processdescribed in this invention are small molecules and are, thus, similarto actual human therapeutics (small molecule drugs).

In one embodiment, a member of a combinatorial library is identified asa ligand for a particular biomolecule using the method described above.The ligand can then be assessed in an in vitro assay for the effect ofthe binding of the ligand to the biomolecule on the function of thebiomolecule. For a biomolecule having a known function, the assay caninclude a comparison of the activity of the biomolecule in the presenceand absence of the ligand. If the biomolecule is of unknown function, acell which expresses the biomolecule can be contacted with the ligandand the effect of the ligand on the viability or function of the cell isassessed. The in vitro assay can be, for example, a cell death assay, acell proliferation assay or a viral replication assay. For example, ifthe biomolecule is a protein expressed by a virus, the a cell infectedwith the virus can be contacted with a ligand for the protein. Theaffect of the binding of binding of the ligand to the protein on viralviability can then be assessed.

A ligand identified by the method of the invention can also be assessedin an in vivo model or in a human. For example, the ligand can beevaluated in an animal or organism which produces the biomolecule. Anyresulting change in the health status (e.g., disease progression) of theanimal or organism can be determined.

For a biomolecule, such as a protein or a nucleic acid molecule, ofunknown function, the effect of a ligand which binds to the biomoleculeon a cell or organism which produces the biomolecule can provideinformation regarding the biological function of the biomolecule. Forexample, the observation that a particular cellular process is inhibitedin the presence of the ligand indicates that the process depends, atleast in part, on the function of the biomolecule.

The mass-coded libraries provided by the present method enable thedevelopment of an information set that describes how the universe ofsmall molecules interacts with any biomolecule encoded within the humanand other genomes. This information set would include data regarding: 1)those libraries and components therein which bind to the targetbiomolecule, 2) quantitative structure-activity relationships (SAR) onchemical functionalities which contribute to the binding affinity of acompound for a biomolecule target, and 3) the domains of the biomoleculethat are bound by chemical compounds. The database can be used toexpedite drug development in a number of ways, for example, byidentifying chemical pharmacophores that interact with high affinitywith a specific drug binding site.

The invention will now be further and more specifically described in thefollowing examples.

EXAMPLES Example 1 Application of Mass-Coding by Computer Algorithms:Comparison of Mass-Coded and Non-Mass-Coded Combinatorial Libraries

The following is an analysis of the application of mass-codingalgorithms towards the design of combinatorial libraries. The sequenceof steps involved in identifying subsets of peripheral moiety precursorsthat can be allowed to react with a predetermined scaffold precursor toyield a mass-coded combinatorial library of compounds with the molecularformula X(Y)_(n) is shown in FIG. 1A; FIG. 1B is an alternate sequenceof steps. It is to be understood that the molecular mass sum of thecombination of the n peripheral moieties in a particular compound of theformula X(Y)_(n) is the collective contribution of the n peripheralmoieties to the molecular mass of the compound. As each compound withinthe library includes a constant scaffold, the mass redundancy of themass-coded library is equivalent to the molecular mass sum redundancy ofall combinations of n peripheral moieties derived from the identifiedsubset of peripheral moiety precursors.

The mass-coding analysis was performed on the initial set of 22peripheral moieties shown below. This initial set was selectedarbitrarily. Included were peripheral moiety precursors having the sameexact mass. The master set consisted of the peripheral moiety precursorsshown below, along with the exact masses of the resulting peripheralmoieties. The molecular masses given are the exact molecular masses andnot the isotope averages. The exact molecular masses are also adjustedfor any atoms which are lost as a result of the reaction with thescaffold precursor (in this case the loss of a hydrogen atom). From theinitial set of 22 peripheral moiety precursors, two sets of 16peripheral moiety precursors were generated. One set was chosen by thecomputer using the mass coding algorithm described herein (computerselected set). The other set was randomly chosen.

From each set of 16 peripheral moiety precursors the computer generatedevery possible subset of 12 peripheral moiety precursors. These subsetswere used to generate all combinations of peripheral moiety precursorstaken 4 at a time (representing libraries synthesized with a scaffoldprecursor having four reactive groups, such as four pentafluorophenylesters). This process yielded two sets of 16 peripheral moietyprecursors containing 1820 subsets of 12 each. Theoretically, thesesubsets of 12 peripheral moiety precursors would each yield a library of1365 compounds containing different peripheral moiety combinations whenallowed to react simultaneously with an appropriate scaffold precursorcontaining four reactive groups (15!/[(15−4)!*4!]=1365). The computersorted every precursor subset and checked for mass redundancy in theresultant libraries (in this example mass redundancies were checked tothe second significant digit after the decimal point).

It is noteworthy that the mass coding algorithms and the mass redundancycheck are both flexible in that it is possible to adjust thecomputational filter to check mass redundancy to any significant figure.This architecture for mass-coding allows for rapid automatedmass-coding, insures that a significant portion of the librariesgenerated with the computer selected set have less than 10% redundancy,and includes parameters for peripheral moiety precursor selectionoutside of exact mass. The computational requirements for this selectionare fairly significant. The mass-coding algorithms are essential becauseit is computationally intractable to brute force calculate and checkevery possible set of peripheral moiety precursors from a master set of60 or more peripheral moiety precursors.

Results

The computer selected set of 16 peripheral moiety precursors contained86 a, 79 a, 13 a, 108 a, 76 a, 20 a, 69 a, 1 a, 70 a, 26 a, 24 a, 36 a,97 a, 94 a, 104 a, and 21 a. The set of 16 randomly chosen peripheralmoiety precursors contained 79 a, 13 a, 20 a, 69 a, 1 a, 26 a, 24 a, 104a, 52 a, 54 a, 19 a, 77 a, 53 a, 21 a, 55 a, 36 a. The librariesgenerated from the computer selected set of peripheral moiety precursorshad an average mass redundancy of 11.5% per library with 234 librarieshaving mass redundancies of less than 5% and 972 libraries having massredundancies of less than 10% (FIG. 2A). The libraries generated fromthe randomly chosen set of peripheral moiety precursors had an averagemass redundancy of 60.7% with no libraries having a mass redundancy ofless than 10% (FIG. 2B). A direct graphical comparison of the massredundancies of the two sets of libraries is shown in FIG. 2C. Thelibraries derived from the computer-selected set of peripheral moietyprecursors and the corresponding mass redundancies are listed in theTable below.

Example 2 Development of Ligands for a Monofunctional Protein

A mass-coded combinatorial library can be used to identify ligands thathave a high affinity for a monofunctional protein. One suchmonofunctional protein is the serine protease trypsin. Ligands thatexhibit a high affinity for trypsin would be candidates to screenfurther for their ability to inhibit the proteolytic activity oftrypsin. The identification of ligands to trypsin involves the followingsteps: trypsin is covalently biotinylated by incubation of the proteinwith a chemically activated biotin precursor. The biotin-trypsinconjugate is immobilized by binding to a streptavidin-derivatizedwater-insoluble column matrix. The mass-coded combinatorial library issolubilized in an appropriate binding buffer and injected onto a columncontaining the trypsin+streptavidin complex. Compounds that do not bindto the column are washed off with binding buffer. Compounds that bind tothe column are dissociated by a change in the buffer conditions, such asa change in the pH or an increase in the percentage of organic solvent.These compounds are then loaded onto a reversed-phase column that isplaced downstream of the trypsin+streptavidin column. The compounds areeluted from the reversed-phase column and analyzed by mass spectrometry.Molecular masses that correspond to ligands for trypsin are identifiedby eliminating those masses which are also observed when the library issimilarly screened with a streptavidin column. The molecular mass ofeach trypsin ligand identifies one combination of peripheral moietiesplus scaffold. The individual compound or compounds that result from theidentified combination of peripheral moieties plus scaffold aresynthesized and tested for their in vitro activity as inhibitors oftrypsin.

Example 3 Development of Ligands for a Multifunctional Protein

Many proteins, especially human proteins, are multifunctional, and thesefunctions are often mediated through interactions with multipleproteins. Ligands that bind to different sites on the protein mighttherefore yield different therapeutic results. The human protein HSP70is one such example of a multifunctional protein. HSP70 has been shownto interact with multiple polypeptides, which are largely unfolded, tofacilitate their translocation and folding. This role of HSP70 has beenimplicated in a variety of physiological processes, including antigenprocessing/presentation, development of certain cancers, and replicationof a variety of human viruses. A mass-coded combinatorial library can beused to identify ligands that have a high affinity for HSP70 and bind atdifferent sites. These ligands for HSP70 can be further evaluated insecondary assays to establish their effects on the immune response,cancer progression, and viral infection.

The identification of ligands to HSP70 involves the following steps:HSP70 is covalently biotinylated by incubation of the protein with achemically activated biotin precursor. The biotin-HSP70 conjugate isimmobilized by binding to a streptavidin-derivatized water-insolublecolumn matrix. The mass-coded library is solubilized in an appropriatebinding buffer and injected onto a column containing theHSP70-streptavidin complex. Compounds that do not bind to the column arewashed off with binding buffer. Compounds that bind to the column aredissociated by a change in the buffer conditions, such as a change inthe pH or an increase in the percentage of organic solvent. Compoundsthat are dissociated from the column are loaded onto a reversed-phasecolumn that is placed downstream of the HSP70-streptavidin column.Compounds are eluted from the reversed-phase column and analyzed by massspectrometry. Masses that correspond to ligands for HSP70 are identifiedby eliminating those masses which are also observed when the library issimilarly screened with a streptavidin column. The mass of each HSP70ligand identifies one combination of peripheral moieties plus scaffold.The individual compound(s) that result from the identified combinationof peripheral moieties plus scaffold are synthesized and tested fortheir in vivo ability to affect the immune response, cancer progression,and viral infection.

Example 3 Development of Ligands that Affect the Binding of a KnownLigand to a Protein

It is often the situation that a biologically important ligand is knownfor a target protein, but development of a high-throughput screen formolecules that modulate the binding of that ligand is not practical. Forinstance, it is known that HSP70 binds unfolded polypeptides in thepresence of ADP, and that the binding of ATP to HSP70 leads to thedissociation of the polypeptide. Mass-coded combinatorial libraries canbe used in the discovery of small molecule ligands that affect thebinding of ATP, ADP, or unfolded peptides to HSP70, and oneconfiguration is listed below: HSP70 is covalently biotinylated byincubation of the protein with a chemically activated biotin precursor.The biotin-HSP70 conjugate is immobilized by binding to astreptavidin-derivatized water-insoluble column matrix. The mass-codedlibrary is solubilized in an appropriate binding buffer and injectedonto a column containing the HSP70-streptavidin complex. Compounds thatdo not bind to the column are washed off with binding buffer. Compoundsthat bind to the column are dissociated upon addition of ATP, ADP, orADP plus an unfolded peptide. Only compounds that bind to the same siteson HSP70 as these known ligands will be eluted under these conditions.Compounds that are dissociated from the column are loaded onto areversed-phase column that is placed downstream of theHSP70-streptavidin column. Compounds are eluted from the reversed-phasecolumn and analyzed by mass spectrometry. Masses that correspond toligands for HSP70 are identified by eliminating those masses which arealso observed when the library is similarly screened with a streptavidincolumn. The mass of each HSP70 ligand identifies one combination ofperipheral moieties plus scaffold. The individual compound(s) thatresult from the identified combination of peripheral moieties plusscaffold are synthesized and tested in vitro for the ability to competewith these known ligands to HSP70 and for their in vivo ability toaffect the immune response, cancer progression, and viral infection.

Example 4 Discovery of Small Molecule Replacements for ProteinTherapeutics

In some instances, the known ligand to a target protein is in factanother protein, and the binding of these two proteins confers atherapeutic benefit. An example of such an interaction is the binding ofgranulocyte colony stimulating factor (G-CSF) to the G-CSF receptor(G-CSF-R). Replacement of G-CSF with a non-peptide small molecule can beundertaken using a mass-coded combinatorial library, and one approach isdetailed below: in two separate and parallel experiments, the mass-codedlibrary is solubilized in an appropriate binding buffer and incubatedwith either the G-CSF-R alone or the G-CSF-R plus G-CSF. Compounds thatbind to the protein(s) are separated from the unbound compounds by rapidsize exclusion chromatography. The binding compounds are loaded with theprotein(s) onto a reversed-phase column that is placed downstream of thesize exclusion column. The binding compounds are dissociated from theprotein(s) and are eluted from the reversed-phase column and analyzed bymass spectrometry. Masses that correspond to compounds that bind to theG-CSF/G-CSF-R interface are identified as those masses which are onlyobserved when the library is screened with G-CSF-R alone; masses whichare also observed in the screen with the G-CSF/G-CSF-R complex areignored. The mass of each interface-specific compound identifies onecombination of peripheral moieties plus scaffold. The individualcompound(s) that result from the identified combination of peripheralmoieties plus scaffold are then synthesized and tested for their invitro or in vivo ability to mimic G-CSF.

Example 5 Development of Small Molecules that Dimerize Two Proteins

Certain therapeutic proteins, such as erythropoietin (EPO), aremultivalent and act by binding two molar equivalents of the targetprotein, thereby dimerizing the target protein, which, in the case ofEPO is the EPO receptor (EPO-R). The protein replacement strategyoutlined in Example 3 can be extended to yield non-peptide compoundsthat act therapeutically by inducing the dimerization of two EPO-Rmolecules. In two separate and parallel experiments, the mass-codedlibrary is solubilized in an appropriate binding buffer and incubatedwith either EPO-R alone or EPO-R plus EPO. Compounds that bind to theprotein(s) are separated from the unbound compounds by rapid sizeexclusion chromatography. The bound compounds are loaded with theprotein(s) onto a reversed-phase column that is placed downstream of thesize exclusion column. The bound compounds are dissociated from theprotein(s) and are eluted from the reversed-phase column and analyzed bymass spectrometry. Masses that correspond to compounds that bind to theEPO/EPO-R interface are identified as those masses which are observedonly when the library is screened with EPO-R alone; masses which arealso observed in the screen with the EPO/EPO-R complex are ignored. Themass of each interface-specific compound identifies one combination ofperipheral moieties plus scaffold. The individual compound(s) thatresult from the identified combination of peripheral moieties plusscaffold are synthesized and tested for their in vitro ability to bindto the target protein, EPO-R. Those compounds exhibiting the highestaffinity for the target protein are compared to identify similaritiesamong them. Ideally, it is observed that one site of derivatization onthe scaffold is relatively unimportant for high affinity binding. Theperipheral moiety at this site is subsequently replaced with a covalenttether that joins two molecules of the highest affinity compound toyield a non-peptide compound that dimerizes the target protein, EPO-R.

Example 6 Simultaneous Target Validation and Small-Molecule DrugDiscovery

An example of a class of target proteins whose roles in a diseaseprocess can be validated by application of target-specific ligands to abioassay are the proteins encoded by the open reading frames (ORF) ofthe Herpes Simplex Virus. The identification of ligands to anORF-encoded protein and the use of the resulting ligands to determinethe function of the ORF-encoded protein and its validity as a target foranti-viral drug discovery involves the following steps : the ORF-encodedprotein is covalently biotinylated by incubation of the ORF-encodedprotein with a chemically activated biotin precursor. The ORF-encodedprotein-biotin conjugate is immobilized by binding to astreptavidin-derivatized water-insoluble column matrix. The mass-codedlibrary is solubilized in an appropriate binding buffer and injectedonto a column containing the ORF-encoded protein+streptavidin complex.Compounds that do not bind to the column are washed off with bindingbuffer. Compounds that bind to the column are dissociated by a change inthe buffer conditions, such as a change in the pH or an increase in thepercentage of organic solvent. These compounds are loaded onto areversed-phase column placed downstream of the ORF-encodedprotein+streptavidin column. The binding compounds are eluted from thereversed-phase column and analyzed by mass spectrometry. Molecularmasses that correspond to ligands for the ORF-encoded protein areidentified by eliminating those masses that are also observed when thelibrary is similarly screened with a streptavidin column. The molecularmass of each ligand for the ORF-encoded protein identifies onecombination of peripheral moieties plus scaffold. The individualcompound(s) that result from the identified combination of peripheralmoieties plus scaffold are synthesized and tested for their ability toinhibit the replication or transmission of the virus in a mammalian cellbioassay or animal model.

The observation of a virus-specific inhibitory activity implicates theORF-encoded protein as a critical component of the viral disease processand confirms that the ORF-encoded protein is specifically amenable tosmall molecule anti-viral drug discovery. Observation of a directcorrelation between the relative binding affinities of the ORF-encodedprotein-specific ligands and the relative inhibitory concentrations ofthe ORF-encoded protein-specific ligands further strengthens theidentification of the ORF-encoded protein as a target for small moleculeanti-viral drug discovery.

Example 7 Development of Small Molecules that can be Applied to theAffinity Purification of a Target Protein

A mass-coded combinatorial library can be used to identify ligands thathave a high affinity for a target protein. One such target protein ishuman erythropoietin (EPO), which is expressed and purified industriallyfor use as a therapeutic drug. Ligands that exhibit a high affinity forEPO can be immobilized on a solid support to generate an EPO-specificaffinity matrix.

The identification of ligands to EPO and the construction of anEPO-specific affinity matrix involves the following steps: the masscoded library is solubilized in an appropriate binding buffer andincubated with the EPO protein. Compounds that bind to the EPO proteinare separated from the unbound compounds by rapid size exclusionchromatography. These compounds are loaded with the EPO protein onto areversed-phase column that is placed downstream of the size exclusioncolumn. The compounds are dissociated from the EPO protein and areeluted from the reversed-phase column and analyzed by mass spectrometry.The molecular mass of each EPO protein-specific ligand identifies onecombination of peripheral moieties plus scaffold. The individualligand(s) that result from the identified combination of peripheralmoieties plus scaffold are synthesized and tested for their in vitroability to bind to the EPO protein. Compounds exhibiting the highestaffinity for the EPO protein are compared to identify similaritiesbetween the compounds. If it is observed that one reactive site on thescaffold is relatively unimportant for high affinity binding, theperipheral moiety at this site is subsequently replaced with a covalenttether that joins the EPO-specific ligand to a water insoluble matrix,thereby generating an EPO-specific affinity matrix.

Alternatively, the covalent tether is used to join the EPO-specificligand to a another molecule, such as biotin, which possesses a highaffinity for a commercially available affinity matrix(streptavidin-derivatized agarose). The biotin-streptavidin interactionis used as a strong, non-covalent immobilization technique.

Example 8 Development of Small Molecules that can be Applied to theVisualization of a Target Protein

A mass-coded combinatorial library can be used to identify ligands thathave a high affinity for a target protein. One such target protein isthe human protein telomerase, the expression of which is linked tocancer progression and aging. Ligands that exhibit a high affinity fortelomerase can be functionalized with a radioactive or non-radioactivetag to thereby generate a telomerase-specific affinity probe forvisualization of the enzyme in vitro or in vivo. The identification ofligands to telomerase and the construction of a telomerase-specificaffinity probe would involve the following steps: a mass-coded libraryis solubilized in an appropriate binding buffer and incubated withtelomerase protein alone. Compounds that bind to the telomerase proteinare separated from the unbound compounds by rapid size exclusionchromatography. The binding compounds are loaded with the telomeraseprotein onto a reversed-phase column that is placed downstream of thesize exclusion column. The compounds are dissociated from the telomeraseprotein and are eluted from the reversed-phase column and analyzed bymass spectrometry mass of each telomerase protein-specific ligandidentifies one combination of peripheral moieties plus scaffold. Theindividual ligand(s) that result from the identified combination ofperipheral moieties plus scaffold are synthesized and tested for theirin vitro ability to bind to the telomerase protein. Compounds exhibitingthe highest affinity for the telomerase protein are compared to identifysimilarities between the compounds. Ideally, it is observed that onereactive site on the scaffold is relatively unimportant for highaffinity binding. The peripheral moiety at this site is subsequentlyreplaced with a covalent tether that joins the telomerase-specificligand to a radioactive moiety or a non-radioactive moiety such as afluorophore, thereby generating a telomerase-specific affinity probe.

Equivalents

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the spirit and scope of theinvention as defined by the appended claims. Those skilled in the artwill recognize or be able to ascertain using no more than routineexperimentation, many equivalents to the specific embodiments of theinvention described specifically herein. Such equivalents are intendedto be encompassed in the scope of the claims. TABLE Field1 1 2 3 4 5 6 78 9 10 11 12 2.197802 86a 79a 13a 108a 76a 20a 1a 70a 26a 94a 21a 97a2.490843 86a 108a 76a 69a 1a 70a 26a 24a 36a 94a 21a 97a 2.637363 86a13a 108a 76a 69a 1a 70a 26a 24a 36a 94a 97a 2.783883 86a 79a 13a 108a76a 20a 69a 1a 70a 26a 94a 21a 2.783883 86a 79a 13a 108a 76a 20a 69a 1a70a 36a 94a 21a 2.783883 86a 13a 108a 76a 20a 69a 1a 70a 24a 36a 94a 97a2.783883 86a 79a 13a 108a 76a 70a 26a 24a 36a 94a 21a 97a 2.930403 86a13a 108a 76a 20a 69a 1a 70a 36a 94a 21a 97a 2.930403 86a 13a 108a 76a 1a70a 26a 24a 36a 94a 21a 97a 2.930403 86a 13a 108a 76a 69a 1a 70a 26a 36a94a 21a 97a 2.930403 86a 79a 13a 108a 76a 20a 69a 1a 70a 26a 24a 104a3.003663 86a 79a 13a 108a 76a 20a 69a 70a 26a 24a 94a 104a 3.003663 86a79a 13a 108a 20a 69a 1a 70a 36a 94a 21a 97a 3.076923 86a 13a 108a 76a20a 69a 1a 70a 26a 24a 94a 97a 3.076923 86a 13a 108a 76a 69a 1a 70a 26a24a 36a 94a 104a 3.076923 86a 13a 108a 76a 20a 69a 1a 70a 26a 94a 21a97a 3.076923 86a 108a 76a 20a 69a 1a 70a 24a 36a 94a 104a 97a 3.07692379a 13a 108a 76a 20a 69a 1a 70a 36a 94a 21a 97a 3.076923 86a 79a 13a108a 76a 20a 69a 70a 26a 94a 104a 21a 3.076923 86a 79a 13a 108a 76a 20a1a 70a 36a 94a 21a 97a 3.223443 86a 13a 108a 76a 69a 1a 70a 26a 36a 94a104a 21a 3.223443 86a 79a 13a 108a 76a 69a 1a 70a 26a 94a 104a 21a3.223443 86a 79a 13a 108a 20a 69a 1a 70a 24a 36a 94a 97a 3.369963 86a79a 13a 108a 20a 69a 1a 70a 26a 94a 21a 97a 3.369963 86a 13a 108a 76a20a 69a 1a 70a 26a 94a 104a 21a 3.369963 86a 79a 13a 108a 76a 20a 1a 70a26a 94a 104a 21a 3.516484 86a 13a 108a 76a 20a 69a 1a 70a 26a 24a 36a97a 3.516484 86a 79a 13a 108a 20a 69a 1a 70a 26a 24a 94a 97a 3.51648486a 13a 108a 76a 20a 69a 1a 70a 26a 24a 94a 104a 3.516484 86a 79a 13a108a 76a 20a 69a 1a 70a 26a 104a 21a 3.516484 86a 13a 108a 76a 20a 69a1a 70a 26a 36a 21a 97a 3.663004 86a 79a 13a 108a 76a 20a 69a 1a 70a 26a94a 104a 3.663004 79a 13a 108a 76a 69a 1a 70a 36a 94a 104a 21a 97a3.663004 79a 13a 108a 76a 20a 1a 70a 26a 94a 104a 21a 97a 3.663004 86a79a 108a 76a 69a 70a 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36a 94a 104a 21a 97a20.3663 13a 108a 20a 69a 1a 26a 24a 36a 94a 104a 21a 97a 20.3663 86a 79a108a 76a 20a 1a 70a 26a 24a 36a 94a 21a 20.3663 79a 13a 108a 76a 20a 69a1a 26a 24a 36a 94a 21a 20.43956 86a 108a 76a 20a 70a 26a 24a 36a 94a104a 21a 97a 20.43956 86a 79a 13a 76a 20a 69a 1a 26a 24a 36a 104a 21a20.51282 79a 13a 20a 69a 1a 70a 26a 24a 36a 94a 21a 97a 20.51282 86a 79a108a 76a 20a 1a 26a 24a 94a 104a 21a 97a 20.58608 79a 108a 76a 20a 1a70a 26a 24a 36a 94a 104a 21a 20.58608 79a 108a 20a 69a 1a 26a 24a 36a94a 104a 21a 97a 20.58608 86a 79a 108a 20a 69a 70a 26a 24a 36a 94a 104a21a 20.58608 86a 13a 76a 20a 69a 70a 26a 24a 36a 94a 104a 21a 20.6593479a 108a 20a 69a 1a 70a 26a 24a 36a 104a 21a 97a 20.65934 79a 20a 69a 1a70a 26a 24a 36a 94a 104a 21a 97a 20.65934 79a 108a 76a 20a 69a 1a 26a24a 36a 94a 104a 21a 20.7326 86a 79a 13a 108a 20a 69a 1a 26a 24a 36a104a 21a 20.7326 86a 79a 108a 20a 1a 70a 26a 24a 36a 104a 21a 97a20.7326 86a 79a 76a 20a 69a 1a 26a 24a 36a 104a 21a 97a 20.7326 86a 79a108a 76a 20a 69a 1a 24a 94a 104a 21a 97a 20.7326 79a 13a 108a 20a 69a 1a70a 26a 24a 36a 104a 21a 20.95238 86a 79a 108a 20a 69a 1a 26a 24a 36a104a 21a 97a 21.02564 86a 13a 108a 76a 20a 69a 26a 24a 36a 94a 104a 21a21.02564 86a 79a 108a 20a 69a 26a 24a 36a 94a 104a 21a 97a 21.0989 86a20a 69a 1a 70a 26a 24a 36a 94a 104a 21a 97a 21.24542 86a 108a 76a 20a69a 26a 24a 36a 94a 104a 21a 97a 21.24542 86a 79a 108a 76a 20a 69a 1a26a 24a 36a 94a 21a 21.31868 86a 79a 13a 76a 20a 1a 26a 24a 36a 94a 104a21a 21.31868 86a 79a 13a 108a 20a 1a 26a 24a 36a 94a 104a 21a 21.3919486a 79a 76a 20a 1a 70a 26a 24a 36a 94a 104a 21a 21.4652 13a 108a 20a 69a70a 26a 24a 36a 94a 104a 21a 97a 21.4652 86a 79a 20a 69a 1a 70a 26a 24a36a 94a 21a 97a 21.4652 86a 79a 13a 76a 20a 69a 26a 24a 36a 94a 104a 21a21.53846 86a 108a 20a 69a 70a 26a 24a 36a 94a 104a 21a 97a 21.61172 86a79a 13a 108a 20a 26a 24a 36a 94a 104a 21a 97a 21.61172 86a 79a 76a 20a69a 1a 26a 24a 36a 94a 21a 97a 21.61172 86a 79a 13a 20a 69a 1a 70a 26a24a 36a 104a 21a 21.61172 86a 79a 13a 108a 20a 70a 26a 24a 36a 94a 104a21a 21.68498 86a 13a 20a 1a 70a 26a 24a 36a 94a 104a 21a 97a 21.6849886a 13a 108a 20a 69a 70a 26a 24a 36a 94a 104a 21a 21.68498 79a 13a 20a69a 1a 70a 26a 24a 36a 104a 21a 97a 21.75824 86a 79a 76a 20a 1a 26a 24a36a 94a 104a 21a 97a 21.75824 86a 13a 76a 20a 69a 1a 26a 24a 36a 94a104a 21a 21.75824 86a 13a 20a 69a 70a 26a 24a 36a 94a 104a 21a 97a21.75824 86a 79a 13a 108a 20a 69a 26a 24a 36a 94a 104a 21a 21.8315 79a13a 108a 20a 69a 1a 26a 24a 36a 104a 21a 97a 21.90476 86a 13a 108a 20a69a 1a 26a 24a 36a 94a 104a 21a

1-33. (canceled)
 34. A method for identifying a member of a mass-codedcombinatorial library which is a ligand for a first biomolecule but isnot a ligand for a second biomolecule, said mass-coded molecular librarycomprising compounds of the general formula XY_(n), wherein n is aninteger from 2 to about 6, X is a scaffold and each Y is, independently,a peripheral moiety, wherein said mass-coded combinatorial library isproduced by reacting a scaffold precursor with a sufficient number ofdistinct peripheral moiety precursors such that there exist at leastabout 250 distinct combinations of n peripheral moieties derived fromsaid peripheral moiety precursors, said method comprising the steps of:(a) contacting the first biomolecule with the mass-coded molecularlibrary, whereby members of the mass-coded molecular library, which areligands for the first biomolecule bind to the first biomolecule to formfirst biomolecule-ligand complexes and members of the mass-coded librarywhich are not ligands for the first biomolecule remain unbound; (b)separating the first biomolecule-ligand complexes from the unboundmembers of the mass-coded molecular library; (c) dissociating the firstbiomolecule-ligand complexes; (d) determining the molecular mass of eachligand for the first biomolecule; (e) contacting the second biomoleculewith the mass-coded molecular library, whereby members of the mass-codedmolecular library which are ligands for the second biomolecule bind tothe second biomolecule to form second biomolecule-ligand complexes andmembers of the mass-coded library which are not ligands for the secondbiomolecule remain unbound; (f) separating the second biomolecule-ligandcomplexes from the unbound members of the mass-coded molecular library;(g) dissociating the second biomolecule-ligand complexes; (h)determining the molecular mass of each ligand for the secondbiomolecule; and (i) determining which molecular mass or massesdetermined in step (d) are not determined in step (h), thereby providingthe molecular masses of members of the mass-coded combinatorial librarywhich are ligands for the second biomolecule, wherein the each molecularmass determined in step (i) corresponds to a set of n peripheralmoieties present in a ligand for the first biomolecule which is not aligand for the second biomolecule, thereby identifying a member of themass-coded combinatorial library which are ligands for the firstbiomolecule but are not ligands for the second biomolecule.
 35. Themethod of claim 34 wherein the first and second biomlecules are each,independently, a protein or a nucleic acid molecule.
 36. The method ofclaim 35 wherein the first and second biomolecules are each a proteinand amino acid sequence of the second biomolecule is derived from theamino acid sequence of the first biomolecule by insertion, deletion orsubstitution of one or more amino acid residues.
 37. The method of claim35 wherein the first biomolecule is a first protein and the secondbiomolecule is a second protein, said first and second proteins havingthe same amino acid sequence, wherein said first and second proteinshave different posttranslational modifications.
 38. The method of claim37 wherein the first protein differs from the second protein in extentof phosphorylation, glycosylation or ubiwuitination.
 39. The method ofclaim 35 wherein the second biomolecule is a complex of the firstbiomolecule with a ligand.
 40. The method of claim 35 wherein the firstand second biomolecules are each immobilized on a solid support.
 41. Themethod of claim 40 wherein the solid support is a water-insoluble matrixcontained within a chromatographic column.
 42. The method of claim 35wherein a solution comprising the first biomolecule is contacted withthe mass-coded molecular library to form a solution comprising firstbiomolecule-ligand complexes and unbound members of the mass-codedmolecular library and a solution comprising the second biomolecularlibrary to form a solution comprising second biomolecule-ligandcomplexes and unbound members of the mass-coded molecular library. 43.The method of claim 42 wherein the unbound members of the mass-codedmolecular library are separated from the second biomolecule-ligandcomplexes by directing the solution comprising second biomolecule-ligandcomplexes and the unbound members of the mass-coded molecular librarythrough a size exclusion chromatography column, whereby the unboundmembers of the mass-coded molecular library elute from second columnafter the second biomolecule-ligand complexes.
 44. The method of claim42 wherein the unbound members of the mass-coded molecular library areseparated from the second biomolecule-ligand complexes by contacting thesolution comprising second biomolecule-ligand complexes and the unboundmembers of the mass-coded molecular library with a size-exclusionmembrane, whereby the unbound compounds pass through said membrane andthe second biomolecule-ligand complexes do not pass through saidmembrane. 45-50. (canceled)